EP0163317B1 - Dérivés de la quinone, procédé de préparation, leur application et composition pharmaceutique - Google Patents

Dérivés de la quinone, procédé de préparation, leur application et composition pharmaceutique Download PDF

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Publication number
EP0163317B1
EP0163317B1 EP85106732A EP85106732A EP0163317B1 EP 0163317 B1 EP0163317 B1 EP 0163317B1 EP 85106732 A EP85106732 A EP 85106732A EP 85106732 A EP85106732 A EP 85106732A EP 0163317 B1 EP0163317 B1 EP 0163317B1
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EP
European Patent Office
Prior art keywords
formula
compound
pharmaceutical composition
compounds
quinone derivatives
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP85106732A
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German (de)
English (en)
Other versions
EP0163317A1 (fr
Inventor
Takayuki Ozawa
Morimitsu Nishikimi
Hiroshi Suzuki
Yoshiharu Shimomura
Isao Yamatsu
Shinya Abe
Hiroshi Yamada
Tohru Fujimori
Tadanobu Takamura
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nagoya University NUC
Original Assignee
Nagoya University NUC
Eisai Co Ltd
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Publication date
Application filed by Nagoya University NUC, Eisai Co Ltd filed Critical Nagoya University NUC
Priority to AT85106732T priority Critical patent/ATE36699T1/de
Publication of EP0163317A1 publication Critical patent/EP0163317A1/fr
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Publication of EP0163317B1 publication Critical patent/EP0163317B1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups

Definitions

  • the invention relates to novel quinone derivatives, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the same.
  • the quinone derivatives of the invention provide a phospholipase inhibition effect, an antiplatelet effect and a therapeutic and/or preventive effect to cardiac diseases.
  • the invention also relates to the use of the novel quinone derivatives for preparing a pharmaceutical composition.
  • the invention provides a process for manufacturing the novel quinone derivatives.
  • Ubidecarenone which is also called coenzyme Q 10 or ubiquinone 1o , was isolated from mitochondria in bovine cardiac muscle in a crystalline form by Crane et al. in 1957. It widely occurs in vivo, in particular in mitochondria in cells, and is an important constituent of a mitochondrial electron transport system governing energy production.
  • p.76 C44 discloses specific quinone compounds of the general formula in which n is an integer of 1 to 10, R 1 is methyl-methoxy and R2is hydrogen or lower alkyl.
  • the known quinone compounds are hypertensives, lenitives, anti-ulcers, anti-inflammatory agents, diuretics, anti- thrombotics, cerebral circulation improving agents and do show also an activity of regulating prostaglandin biosynthesis and effect to block adrenergic activity response.
  • the present invention comprises a quinone derivative of the formula (I) in which X and Y are either the same as or different from each other and each are hydroxy, methoxy or hydrogen; and n is an integer of 1 to 5, or a pharmaceutically acceptable salt thereof.
  • novel quinone derivative of formula (I) of claim 1 can be prepared by reacting in a manner known per se a compound of the formula (II): in which X and Y have the definition as in formula (I) in claim 1 with a compound of formula (III): in which n is an integer of 1 to 5 and R is hydrogen or a lower alkyl group.
  • the reaction is carried out in the presence of a catalyst such as silica gel/zinc chloride.
  • R in formula (III) represents a lower alkyl group, it may be hydrolyzed with caustic potash or caustic soda to form a carboxylic acid.
  • the compound of the present invention exhibits a remarkably excellent phospholipase inhibition effect as well as antiplatelet effect, which makes it useful, e.g. as an antiplatelet, a blood compatible agent and a therapeutic agent for various cardiac diseases. More particularly it is available in treating and/or preventing cerebrovascular diseases such as TIA (transient ischenuc attack), cerebroinfarct (thrombi and emboli) and cerebral arteriosclerosis; postoperative thrombi, emboli and blood stream disorders accompanying vascular operations and extracorporea blood circulation; peripheral blood stream disorders caused by emboli or constriction of limb artery such as Buerger's disease, arteriosclerosis obliterans, SLE and Raynaud's disease; congestive failure accompanied by edema, pulmponary congestion or hepatomegaly; and cardiac diseases such as stenocardia and myocardial infarction.
  • the compound of the present invention is further effective in preventing relapse of the foregoing diseases and treating the recuper
  • the compound of the present invention is furthermore effective in treating and/or preventing inflammatory diseases such as various rheumatic diseases.
  • Table 1 shows the result. Each value in Table 1 represents the evaluation of the corresponding compound assuming the value of a physiological saline solution as 100 and indicates the phospholipase A 2 inhibition activity thereof.
  • Platelet agglutination test was carried out in the following manner with the use of PAF (platelet activating factor; 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine), collagen and ADP as inducers.
  • PAF platelet activating factor; 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine
  • collagen and ADP as inducers.
  • Blood was collected from the venae brachiales of a healthy male adult in an amount of nine parts by volume to one part by volume of 3.8% sodium citrate solution. The blood was centrifuged at 100 x g for eight min and PRP separated as the supernatant was collected.
  • Table 2 obviously indicates that the compounds of the present invention exert better antiplatelet effects than that of CoQ 10 .
  • the concentrate was dissolved in 50 ml of ethanol and 3 g of caustic soda was added thereto. After refluxing for 30 min, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, concentrated and purified with silica gel chromatography with the use of ethyl acetate/benzene as the eluent to give 1.7 g of the title compound as a colorless oil.
  • Example 2 The procedures of Example 1 were repeated except that 5 g of 2,3,4-trimethoxy-5-methylphenol and 3.2 g of 20-hydroxy-2,6,10,14,18-pentamethyl-2,6,10,14,18-eicosapentaenoic acid were employed as the starting materials to give 2.8 g of the title compound as a colorless oil.
  • Example 2 The procedures of Example 1 were repeated except that 5 g of 2,3,4-trimethoxy-5-methylphenol and 3.5 g of 24-hydroxy-2,6,10,14,18,22-hexamethyl-2,6,10,14,18,22-tetracosahexaenoic acid were employed as the starting materials to give 2.5 g of the title compound as a colorless oil.
  • Table 3 shows physiochemical properties of the compounds of the present invention as prepared in Examples 1 to 5.
  • the compounds A to G of the present invention were orally administered to male ddY mice of approximately 25 to 30 g in body weight to thereby examine the acute toxicity thereof. Consequently each compound showed LO so of at least 500 mg/kg.
  • the compounds A to G of the present invention were injected into the tail veins of 10 mice as described above in doses of 10, 30 and 100 mg/kg. The mice showed a survival ratio of 100% (i.e. 10/10) in each case, which suggests that the LO so of each compound is at least 100 mg/kg.
  • the compound of the present invention exhibits a phospholipase inhibition effect as well as an antiplatelet effect and may be formulated into drugs such as an antiplatelet, a blood compatible agent and a therapeutic and/or preventive agent for cardiac diseases or inflammatory diseases including rheumatic diseases for oral or parenteral, e.g. intramuscular, hypodermical or intravenous administration or as a suppository.
  • the compounds may be administered to an adult usually in a dose of approximately 10 to 1,000 mg, preferably approximately 50 to 500 mg, per day depending on the disease, condition and age of the patient.
  • the compound of the present invention may be formulated into various forms such as a tablet, granules, a powder, a capsule, an injection or a suppository in a conventional manner.
  • a solid drug for oral administration may be prepared by mixing the active compound(s) with excipient(s) and, if necessary, binder(s), disintegrating agent(s), lubricant(s), colorant(s) and corrigent(s) and formulating the obtained mixture into a tablet, a coated tablet, granules, a powder or a capsule in a conventional manner.
  • excipient lactose, corn starch, sucrose, glucose, sorbitol and crystalline cellulose.
  • binder polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, gum arabic, gum tragacanth, gelatin, shellac wax, hydroxypropylcellulose, hydroxypropylstarch and polyvinylpyrrolidone.
  • disintegrating agent starch, agar, powdery gelatin, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin and pectin.
  • lubricant are magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils.
  • compositions may be added.
  • examples of the corrigent are cacao powder, peppermint extract, aromatic acids, peppermint oil, Borneo camphor and cinnamon powder.
  • the tablet or granules thus prepared may be optionally coated with an appropriate material such as sugar or gelatin.
  • a hypodermical, intramuscular or intravenous injection may be prepared by adding desired pH adjustor(s), solubilizer(s), suspending agent(s), buffer(s), stabilizer(s), and preservative(s) to the active compound(s) and treated the mixture in a conventional manner.
  • the ingredients as shown above were formulated into granules in a conventional manner and packed in gelatin hard capsules.
  • the compound B, Nikkol HCO-60, sesame oil and a half amount of the propylene glycol were mixed together and heated to approximately 80°C for dissolution.
  • Phosphate buffer solution, sodium chloride and the residual propylene glycol previously dissolved in distilled water and heated to approximately 80°C were added thereto to give an aqueous solution of 1,000 ml in total volume. 1 ml portions of the aqueous solution were poured into ampuls, which were then sealed and sterilized by heating.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (4)

1. Dérivé quinonique de formule (I)
Figure imgb0027
dans laquelle X et Y sont soit identiques, soit différents l'un de l'autre, et sont chacun un groupe hydroxy, méthoxy ou un atome d'hydrogène; et n est un nombre entier valant de 1 à 5; ou un sel pharmaceutiquement acceptable de celui-ci.
2. Procédé pour la préparation d'un dérivé quinonique de formule (I) selon la revendication 1, qui comprend l'étape de la mise en réaction, d'une façon connue en soi, d'un composé de formule (II)
Figure imgb0028
dans laquelle X et Y sont tels que définis pour la formule (I) dans la revendication 1, avec un composé de formule (III)
Figure imgb0029
dans laquelle n est un nombre entier valant de 1 à 5, et R est un atome d'hydrogène ou un groupe alkyle inférieur.
3. Composition pharmaceutique comprenant une quantité pharmaceutiquement efficace du dérivé quinonique de formule (I) selon la revendication 1, ou d'un sel pharmaceutiquement acceptable de celui-ci, et un véhicule pharmaceutiquement acceptable.
4. Utilisation du dérivé quinonique de formule (I) selon la revendication 1, pour la préparation d'une composition pharmaceutique.
EP85106732A 1984-05-31 1985-05-31 Dérivés de la quinone, procédé de préparation, leur application et composition pharmaceutique Expired EP0163317B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT85106732T ATE36699T1 (de) 1984-05-31 1985-05-31 Chinonderivate, verfahren zu ihrer herstellung, ihre verwendung und pharmazeutische zusammensetzung.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP59111555A JPS60255749A (ja) 1984-05-31 1984-05-31 キノン誘導体
JP111555/84 1984-05-31

Publications (2)

Publication Number Publication Date
EP0163317A1 EP0163317A1 (fr) 1985-12-04
EP0163317B1 true EP0163317B1 (fr) 1988-08-24

Family

ID=14564354

Family Applications (1)

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EP85106732A Expired EP0163317B1 (fr) 1984-05-31 1985-05-31 Dérivés de la quinone, procédé de préparation, leur application et composition pharmaceutique

Country Status (8)

Country Link
US (1) US4992469A (fr)
EP (1) EP0163317B1 (fr)
JP (1) JPS60255749A (fr)
AT (1) ATE36699T1 (fr)
CA (1) CA1270844A (fr)
DE (1) DE3564566D1 (fr)
IL (1) IL75337A (fr)
SU (2) SU1442068A3 (fr)

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE153655T1 (de) * 1990-02-08 1997-06-15 Eisai Co Ltd Benzensulfonamidderivat
US5393776A (en) * 1990-09-14 1995-02-28 Bristol-Myers Squibb Company Tocotrienol analogs in the treatment of hypercholesterolemia and hyperlipidemia
AU4510596A (en) * 1994-12-06 1996-06-26 National Research Council Of Canada Water soluble ubiquinone compositions, prodrugs, and methods relating thereto
US6458952B1 (en) * 1999-05-19 2002-10-01 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
US6664255B1 (en) * 1999-05-19 2003-12-16 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
US6906068B1 (en) 1999-05-19 2005-06-14 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl 1,2,4 - triazinones useful as anticoagulants
US6908919B2 (en) * 1999-05-19 2005-06-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
US6653316B1 (en) 1999-05-19 2003-11-25 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US6716838B1 (en) 1999-05-19 2004-04-06 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents
US6867217B1 (en) 1999-05-19 2005-03-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
US6750342B1 (en) * 1999-05-19 2004-06-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US7015230B1 (en) 1999-05-19 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
WO2001068605A1 (fr) 2000-03-13 2001-09-20 Pharmacia Corporation Benzenes polycycliques substitues aryle et heteroaryle utiles pour l'inhibition selective de la cascade de coagulation
WO2001077097A2 (fr) * 2000-04-05 2001-10-18 Pharmacia Corporation 4-pyrones polycycliques a substitution aryle et heteroaryle utiles pour l'inhibition selective de la cascade de coagulation
CA2405306A1 (fr) 2000-04-05 2001-10-18 Pharmacia Corporation Pyridones polycycliques 4-aryl et heteroaryl substituees utiles pour l'inhibition selective de la cascade de coagulation
US20040171616A9 (en) 2000-04-17 2004-09-02 South Michael S. Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade
US7119094B1 (en) 2000-11-20 2006-10-10 Warner-Lambert Company Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade
CA2430037A1 (fr) * 2000-11-20 2002-05-30 Michael S. South Aryl-et-heteroaryl-pyridines polycycliques substituees utiles dans l'inhibition selective de la cascade de la coagulation
US7015223B1 (en) 2000-11-20 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade
US20030236257A1 (en) * 2001-04-04 2003-12-25 South Michael S. Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the cogulation cascade
US20040082585A1 (en) * 2001-10-03 2004-04-29 Pharmacia Corporation Prodrugs of substituted polycyclic compounds useful for selective inhibition of the coagulation cascade
BR0213099A (pt) * 2001-10-03 2004-10-19 Pharmacia Corp Compostos policìclicos de 5 membros substituìdos úteis para inibição seletiva da cascata de coagulação
CA2462305A1 (fr) * 2001-10-03 2003-04-10 Michael S. South Composes heterocycliques a 6 chainons utiles dans l'inhibition selective de la cascade de la coagulation
CA2462647A1 (fr) * 2001-10-03 2003-04-10 Michael S. South Composes heterocycliques insatures a 6 chainons utiles pour l'inhibition selective de reactions en cascade de la coagulation
US20040068113A1 (en) * 2001-11-20 2004-04-08 South Michael S. Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade
WO2005034945A1 (fr) * 2003-10-11 2005-04-21 Thierry Schwitzguebel Utilisation de la norphenazone et de coenzyme q pour le traitement de l'arthrose, l'arthrite et l'osteo-arthrite
JP2006045187A (ja) * 2003-12-25 2006-02-16 Bio Igaku Kenkyusho Kk 臓器不全治療剤
JP2006069958A (ja) * 2004-09-02 2006-03-16 Bio Igaku Kenkyusho Kk 老化防止剤
US7528271B2 (en) * 2007-05-16 2009-05-05 Bergen Teknologioverforing As Intermediates, process for their preparation and synthesis of 1,4-benzoquiones

Family Cites Families (5)

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Publication number Priority date Publication date Assignee Title
US3957836A (en) * 1973-07-02 1976-05-18 Takeda Chemical Industries, Ltd. Quinone derivatives
JPS5640651A (en) * 1979-09-12 1981-04-16 Takeda Chem Ind Ltd Quinone compound and its preparation
JPS567737A (en) * 1979-07-02 1981-01-27 Takeda Chem Ind Ltd Physiologically active quinone and its preparation
JPS5697223A (en) * 1979-12-30 1981-08-05 Takeda Chem Ind Ltd Tissue metabolism activator
JPS58177934A (ja) * 1982-04-13 1983-10-18 Takeda Chem Ind Ltd ベンゾキノン誘導体

Also Published As

Publication number Publication date
CA1270844A (fr) 1990-06-26
IL75337A0 (en) 1985-09-29
ATE36699T1 (de) 1988-09-15
EP0163317A1 (fr) 1985-12-04
US4992469A (en) 1991-02-12
IL75337A (en) 1989-02-28
JPH056533B2 (fr) 1993-01-26
SU1447276A3 (ru) 1988-12-23
JPS60255749A (ja) 1985-12-17
DE3564566D1 (en) 1988-09-29
SU1442068A3 (ru) 1988-11-30

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